Many of the most debilitating neurological disorders, including Alzheimer's disease, schizophrenia, and addiction, drastically affect cognitive function. Functions such as episodic memory and decision-making define an individual's personality and the decline of these functions is debilitating to patients and families. To develop directed therapies to treat deficits in cognitive function, we must understand the neural mechanisms supporting normal cognition. The hippocampus is known to play an important role in episodic memory and spatial navigation, and has recently been implicated in self-projection and imagination. The rodent hippocampus has been an extremely informative model system because it is relatively easy to access with electrodes, and because the firing of hippocampal pyramidal cells has a clear behavioral correlate: the animal's location in an environment. At any given time as an animal moves through an environment, the population of pyramidal cells in the hippocampus is representing the animal's physical location. At choice points in a maze, as an animal demonstrates tentative behaviors suggestive of considering its options, the hippocampal representation of location sweeps forward from the animal's current location down the possible paths it might take. This has been hypothesized to be a mechanism for evaluating the outcome of potential choices. At other times, while the animal is paused and inattentive but awake, the hippocampus replays sequences of neural activity representing behavioral experiences in the order they were experienced (forward replay) and in the reverse order that they were experienced (backward replay). The neural mechanisms supporting backward replay are currently unknown. Replay is thought to be important for consolidating recent memories into long-term memory and for learning general knowledge structures (i.e. cognitive maps) of the environment. In this proposal we investigate the neural basis of the environmental representation maintained by the hippocampus, which enables it to flexibly represent trajectories across the environment. In Specific Aim 1, we will run an experiment to investigate the ability of the hippocampus to represent behavioral sequences across a portion of the environment that was never experienced, thereby testing whether hippocampal representations are driven purely by experience. In Specific Aim 2, we will model the hippocampus to test the hypothesis that a recently discovered theta phase gradient across the hippocampus can be exploited to learn behavioral sequences in the backward order. PUBLIC HEALTH RELEVANCE: This proposal aims to further our understanding of the neural mechanisms underlying cognitive processes supported by the hippocampus, which include episodic memory, spatial navigation, and potentially imagination and self-projection. Disorders involving these cognitive processes are widespread (e.g. Alzheimer's disease and schizophrenia) and deeply affect patients and their families. Studying cognition at the neural level is important for understanding the pathophysiology of these disorders and for developing directed therapies to treat them.